Present dietetic needs and perceptions have led to the increased use of artificial sweeteners as a replacement for the "natural" sugars, including sucrose and fructose. Such artificial sweeteners are highly imperfect, including being under continual review for their long term physiological affects, yet their demand has grown unabated. Accompanying their growth as a commercial area with substantial economic impact has been a renewed emphasis on discovering and supplying new artificial sweeteners.
The ideal artificial sweetener would be noncaloric, noncariogenic, without detrimental physiological effects, and usable by diabetics. All these requirements would be met if a sweetener were not metabolized by humans and by flora which are found in the mouth and intestinal tract, and if the sweetener were either not absorbed by humans, or absorbed without effect on any internal organ. That is, the ideal sweetener should be excreted in the same form as when ingested. Another desirable feature is that it have bulk properties similar to sucrose so that it can be substituted for table sugar in many formulations. Recently, and perhaps belatedly, attention has turned toward the L-sugars as desirable artificial sweeteners. It has been known since at least 1946 that L-fructose is sweet (M. L. Wolfrom and A. Thompson, J. Am. Chem. Soc., 68, 791,793 (1946)), and since at least 1890 that L-fructose is nonfermentable (E. Fischer, Ber. Deutsch. Chem. Ges., 23, 370,389 (1890)), hence not metabolized by microorganisms generally metabolizing D-sugars. A reasonable, although not necessarily correct, inference is that it also is not metabolized by humans. Assuming that L-fructose is a sweet nonmetabolite it becomes obvious to use it as a noncaloric sweetener in many formulations. More recently Shallenberger and coworkers have demonstrated that many L-sugars have a sweetness comparable to their L-enantiomorphs. Nature, 221, 555 (1969). Cf. R. S. Shallenberger, "The Theory of Sweetness," in Sweeteners and Sweetness, pp 42-50. Ed. by G. G. Birch and coworkers; R. S. Shallenberger and T. E. Acree in "The Handbook of Sensory Physiology," Vol. 4, pp 241-245, Edited by L. M. Beider (Springer Verlag, 1971).
Exploitation of the favorable properties of L-sugars is hindered by their relative unavailability. L-Fructose, for example, is not found to any significant extent in nature. This unavailability has spurred recent efforts in developing commercially feasible methods for preparing L-sugars in amounts necessary for their use as a staple of commerce. U.S. Pat. Nos. 4,371,616 and 4,421,568 describe a method of producing L-sugars, including L-idose and L-glucose, from the readily available D-glucose. Although the preparation of a number of L-sugars is described in U.S. Pat. No. 4,262,032 the focus seems to be on typical laboratory methods wholly unsuited for economical industrial production. U.S. Pat. No. 4,440,855 presents a flow scheme for the preparation of a mixture of L-glucose and L-mannose. The subject matter of U.S. Pat. No. 4,207,413 is L-sucrose, the enantiomer of ordinary table sugar, which can be hydrolyzed to afford L-fructose and L-glucose.
Whatever are the details of processes, actual or proposed, for the preparation of L-sugars, most employ a one carbon chain extension of a lower L-monosaccharide to gain entry to the family of L-sugars. Several methods are known for a one carbon chain extension or homologation of carbohydrates generally, and of monosaccharides in particular, including condensation with nitromethane and addition of the elements of hydrogen cyanide to form a mixture of cyanohydrins. Based on such factors as cost and range of applicability, it appears to us that addition of the elements of hydrogen cyanide is best adapted to the homologation of carbohydrates, and more particularly to the homologation of L-monosaccharides.
Addition of the elements of hydrogen cyanide is typically effected by reacting a cyanide salt or hydrogen cyanide with an aldehyde or ketone, here a monosaccharide, under slightly basic conditions to afford a cyanohydrin or a mixture of cyanohydrins. Such a procedure has several inherent disadvantages. One is the human and environmental danger posed by the necessity of handling the extremely toxic cyanides, which is further multiplied where hydrogen cyanide is the cyanide source or where it is generated, even in small quantities, during subsequent product mixture processing. Because the cyanide used often is in substantial excess, another disadvantage arises from the need to remove cyanide from the cyanohydrin, and the greater the cyanide coexistent with the cyanohydrin the more onerous the task. Related to, yet distinct from, the cyanide problem is the relatively high concentration of other salts in the product mixture incident to this procedure. Not only must these salts be removed from the aqueous solution containing cyanohydrin, but they must be disposed of in an environmentally acceptable fashion.
An alternative to the direct addition of hydrogen cyanide as described above is transcyanohydrination, i.e., the reaction where a cyanohydrin acts as a donor of the elements of HCN to an aldehyde or ketone which acts as the acceptor of these elements. Such a reaction, which has been known for some time, can be depicted as, ##STR1## and in principle can afford mixture free of cyanide and of salts generally. Although cyanide- and salt-free products are rarely attained without the benefit of added purification steps, nonetheless transcyanohydrination is characterized by affording a product mixture containing substantially less cyanide and other salts than present from direct addition of hydrogen cyanide.
Transcyanohydrination as a method of homologation of monosaccharides has not been described, yet there is no impediment to its use. Since carbohydrates generally, and monosaccharides particularly, are freely soluble in water but only difficulty soluble in organic solvents, and because there are good reasons to perform reactions homogeneously (vide infra), a water soluble donor cyanohydrin is indicated. This requirement presents no difficulty, for acetone cyanohydrin is an inexpensive, readily available, and quite water soluble material which can be used as a donor cyanohydrin in the homogeneous transcyanohydrination of carbohydrates generally.
The overwhelming preference for conducting reactions in a liquid state homogeneously (i.e., a single phase) is no whim and rests on sound principles recognized, if not understood, by all chemists at an early stage. In a homogeneous liquid system reagent A is readily transported to reactive site B by diffusion; the reaction rate is rarely transport controlled or even transport influenced. Conversely, in a heterogeneous (i.e., two phase) liquid system the variability of the reaction is legion. Characteristics such as reaction rate, product yield, and product distribution often are reflective of poor transport across the phase boundary and are sensitively affected by the degree of mixing of the two phases. Reproducibility by the same worker is erratic, reproducibility by different workers in the same laboratory is uncertain, and interlaboratory reproducibility frequently is unattainable. It is no accident that heterogeneous liquid state reactions are usually avoided wherever possible.
In accord with the foregoing can be mentioned the work of Kung, U.S. Pat. No. 2,259,167, who prepared relatively low molecular weight cyanohydrins by a homogeneous transcyanohydrination process. In U.S. Pat. No. 4,048,210 Davis recognized that whereas transcyanohydrination could be successfully conducted homogeneously in aqueous solution where water soluble cyanohydrins were formed, an analogous procedure was impossible for his water-immiscible benzaldehydes. To avoid the perceived penalties of a heterogeneous reaction, the patentee constructed a homogeneous transcyanohydrination procedure utilizing an organic solvent.
In view of the well-founded bias against liquid two phase reactions as well as the specific teachings of Davis to avoid heterogeneous transcyanohydrination, my discovery that a heterogeneous variant for homologation of carbohydrates, especially monosaccharides, not only works well but is advantageous and actually is preferred over its homogeneous counterpart is particularly unexpected. The invention herein is a method of homologating monosaccharides employing a heterogeneous, two phase liquid system where the water-insoluble donor cyanohydrin is dissolved in an organic solvent immiscible with water and the acceptor monosaccharide is in aqueous solution. Because hydrogen cyanide or a cyanide salt is not handled, our invention represents a significant advance in worker and environmental safety relative to homologation via direct addition of hydrogen cyanide. Another advantage is that there is demonstrably less cyanide in the product than when direct HCN addition is used. Similarly, the product mixture is far lower in inorganic impurities, mainly salts, in part because pH control can be effected by relatively small amounts of dilute mineral or weak organic acids. This latter consideration is important, for surprisingly it has been found to be far more difficult and costly to remove salts from the product mixture than to separate the formed cyanohydrin from unreacted monosaccharide. Another important advantage unique to our invention is that uncomplicated continuous processes can be readily employed and devised using our two phase, heterogeneous homologation, whereas their counterparts are either more complex or impossible with a homogeneous transcyanohydrination.
Although it should be apparent, it needs to be explicitly recognized and understood that our choice of a heterogeneous transcyanohydrination is a conscious, deliberate one rather than one forced upon us by the exigencies of the situation. Given that the acceptor monosaccharides and their cyanohydrins are water soluble materials insoluble in most organic solvents, it is a simple task to construct a homogeneous aqueous transcyanohydrination process using a water soluble donor cyanohydrin such as acetone cyanohydrin, a readily available compound. What we want to emphasize is that despite the availability of a homogeneous transcyanohydrination process for one carbon homologation of monosaccharides our process is heterogeneous, and that we find such a heterogeneous transcyanohydrination advantageous for the reasons stated in the prior paragraph.